The immune system acquired the mechanism that can respond to various foreign antigens. The mechanism takes the diversity of an antigen receptor by recombination of V, (D) and J fragment in T cells and B cells. Although this mechanism brought about a result that produces autoreactive lymphocytes, these autoreactive lymphocytes are removed by the negative selection in thymus or bone marrow, and are further controlled by the self-tolerance mechanism of clonal deletion or anergy in periphery.
Although it is thought that an autoimmune disease is developed by the breakdown of self-tolerance, the researches using various disease murine model have been conducted to elucidate the mechanism of pathogenesis. However, the etiology of an autoimmune disease and the molecular mechanism of self-tolerance remain unclear. In such a situation, existence of the mouse which shows the symptoms of an autoimmune disease caused by a single gene deficient is very important for study the etiology of an autoimmune disease from a molecular biological viewpoint. CTLA4−/−mouse which causes lethal systemic lymphocytes infiltration (Waterhouse P., et al., Science, 270:985-988, 1995, Tivol E. A., et al., Immunity, 3:541-547, 1995), SHP-1 deficient mothaten mice (Shulltz L. D., et al., Cell, 73:1445-1454, 1993), lyn−/−mouse which shows the symptoms of glomerular nephritis (Hibbs M. L., et al., Cell, 83:301-311, 1995), and FCRIIB−/−mouse (Bolland S. & Ravetch J. V., Immunity, 13:277-285, 2000) are the representation, and the relations of these molecules and self-tolerance has been studied.
The PD-1 gene, which belongs to the immunoglobulin super family, encodes a 55 kDa type I transmembrane protein. Both mouse PD-1 and human PD-1 consist of 288 amino acids, and have signal peptide at N terminal (20 amino acid) and hydrophobic region in the middle part, which is a transmembrane region (The EMBO J., 11(11):3887-3895, 1992); Japanese patent Publication No. 5-336973; EMBL/GenBank/DDJB Acc. No. X67914, Genomics, 23:704, 1994; Japanese patent Publication No. 7-291996 (U.S. Pat. No. 5,629,204).
In thymus, PD-1 is expressed at the transition phase between CD4−/CD8− to CD4+/CD8+ stage on thymocytes (Nishimura H., et al., Int. Immunol., 8:773-780 (1996), Nishimura H., et al., J. Exp. Med., 191:891-898 (2000)). In periphery, PD-1 is expressed on T cells and B cells activated through the antigen receptor (Agata Y., et al., Int. Immunol., 8:765-772 (1996)), and on activated myeloid lineage cells such as macrophages.
PD-1 has ITIM (Immunoreceptor tyrosine-based inhibitory motif) in its intracellular region. Therefore, PD-1 is a negative regulator in immune responses. Since PD-1 deficient mice developed a lupus-like glomerular nephritis and arthritis (C57BL/6 genetic background) (Nishimura H., et al., Int. Immunol., 10:1563-1572, 1998, Nishimura H., et al., Immunity, 11:141-151, 1999) and dilated cardiomyopathy-like disease (BALB/c genetic background) (Nishimura H., et al., Science, 291:319-322 (2001)), it became clear that PD-1 serves as a regulator for the development of autoimmune disease, especially for the maintenance of self tolerance. Further it has been reported that graft rejection is regulated by inhibition of PD-1 signal (Journal of Immunology, 169, 11:6543-6553 (2001)).